TRPV1 channels are ligand- and heat-gated ion channels that have a calcium permeability comparable to NMDAR channels. First identified and cloned in primary sensory afferent neurons in the peripheral nervous system, mounting evidence supports the expression and activity of these channels in brain. My laboratory recently published the first functional evidence that TRPV1 channels are present on hippocampal pyramidal cells. Using electrophysiological methods in brain slices, we found that TRPV1 channels are essential for a form of hippocampal synaptic plasticity, the first evidence that any TRP channel is required for synaptic plasticity. The hippocampus is a brain region required for normal formation of new long-term memories. The discovery of a new, highly Ca2+permeable cation channel in hippocampal neurons and its ability to trigger synaptic changes has important implications for hippocampal information processing. Furthermore, the hippocampus is nearly always involved in temporal lobe epilepsy. Our evidence suggests that activation of hippocampal TRPV1 channels will both depolarize the excitatory pyramidal neurons directly, and persistently depress excitatory drive to inhibitory interneurons. This combination of effects is relevant to the development of epilepsy because it is expected to drive the hippocampus into a more excitable state. In this proposal I plan to define the conditions under which hippocampal TRPV1 channels are activated, using as electrophysiological assays both excitability changes in pyramidal neurons and alterations of synaptic function produced by TRPV1 activation. In the peripheral nervous system, TRPV1 has been characterized as a heat-activated ion channel. Although the brain is generally protected from large temperature changes, our preliminary data suggest that hippocampal TRPV1 channels may contribute to heat-activated seizure activity. We will begin to explore the idea that TRPV1 could play a role in febrile seizures, seizures generated in young children during fever for which there is currently no effective treatment. In the proposed experiments, we will test activation of TRPV1 channels by heat and endogenous ligands to begin to identify the conditions under which TRPV1 channels alter hippocampal function. PUBLIC HEALTH RELEVANCE: We have identified for the first time in the hippocampus, a region required for normal learning and memory and frequently implicated in human seizure disorders, a protein called TRPV1 that is activated by heat and natural compounds found in the brain. The heat-sensitivity of TRPV1 suggests that this protein could contribute to fever-induced seizures in young children, a disorder that can progress to epilepsy and that currently has no effective treatment. Here we will explore the novel hypothesis that TRPV1 contributes to hippocampal excitability, and could represent a novel therapeutic target for epileptic seizures.